Project Summary Abstract Outbreaks of Zika Virus (ZIKV) have been recorded in Africa, the Americas, Asia, and the Pacific, and despite significant resources being dedicated to combat ZIKV proliferation, there is no known cure. Many mosquito- borne flavivirus such as ZIKV, Dengue virus, Yellow Fever virus, and West Nile virus have structured 3? UTRs. Structured RNA elements in the 3?UTRs allow the virus to resist degradation by host exonucleases during infection leading to the production of noncoding subgenomic flavivirus RNAs, which are directly linked to cytopathic and pathologic effects by dysregulating RNA decay pathways and binding cellular proteins important for antiviral response. We aim to develop small molecules that target the ZIKV exonuclease resistant RNA to promote ZIKV genome degradation by host exonucleases and inhibit viral proliferation and infection. Successfully demonstrating that flaviviral exonuclease resistant RNAs can be targeted by small molecules to inhibit viral proliferation and infection has the potential to create an entirely new field of anti-flavivral drug discovery and lead to the development of broad spectrum anti-flaviviral therapeutics.